A significant number of patients with acquired immunodeficiency syndrome (AIDS) develops neuropsychiatric complications including dementia (neuroAIDS). In addition to the infiltration of microglias, pathological findings indicate that the extent of neurodegeneration seems to correlate with the amount of the human immunodeficiency type one virus (HIV-1) protein antigen in the brain. We proposed that HIV-1 protease could induce cytotoxicity in the host brain cells, leading to the breakdown of cytoskeleton proteins, organelles and nucleic acids. To test this hypothesis, nanomolar HIV-1-derived protease and envelope protein (gp-120) were added to cultures of human neuroblstoma SH-SY-5Y cells (a serotonin and dopamine containing cell line) and cell viability was measured using trypan blue staining procedure. Similar to earlier reports gp-120 caused a significant cell death. Moreover, the present results reveal that nanomolar HIV-1 protease was as toxic as gp-120 in the human neuroblastoma cells. Significantly, HIV-1 protease induced apoptosis or DNA fragmentation in this cell line. Furthermore, HIV-1 protease-induced cytotoxicity was blocked by Kynostatin (KNI-272), a selective HIV-1 protease inhibitor. This finding indicates that similar to gp-120, HIV-1 protease may cause degeneration of brain cells and neurons that could contribute to the development of neuroAIDS or the AIDS dementia complex.